The subject invention relates to novel N-phenylmethyl-5,6-dihydroimidazo[5,1-a]benzazepin-3-amine compounds, pharmaceutical compositions containing them, and their therapeutic or preventative use in the areas of cardiovascular, oncology, infectious and inflammatory diseases.
Certain imidazo-isoquinoline compounds are disclosed in U.S. Pat. No. 3,917,610 issued Nov. 4, 1975; they are reported to have certain cardiovascular activities. One such compound is further reported on in Borchard, Fox, and Greeff, xe2x80x9cThe Positive Inotropic, Antiarrhythmic and Na+, K+-ATPase Inhibitory Effects of the Isoquinoline Derivative, BIlAxe2x80x9d, Achives of Pharmacology, vol. 312 (1980), pp. 187-192.
The subject invention includes compounds having the structure: 
wherein:
(a) The bond between Cxcex1 and Nxcex2 is a single bond, or a double bond whereby R2 (and H on Cxcex1) are nil;
(b) the bond between C5 and C6 is a single bond, or a double bond whereby R13 and R15 are nil; the bond between C6 and C7 is a single bond, or a doublebond whereby R11 and R13 are nil; but the C5-C6 and C6-C7 bonds are not both double bonds;
(c) R1 is selected from alkyl, aryl, and heterocycle;
(d) R2, if not nil, is selected from hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl and arylsulfonyl;
(e) R3, R4 and R5 are each independently selected from hydrogen, halo, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl- or aryl- or heterocycle-substituted hydroxy, thio, amino, amide, formyl (acyl), carboxy, and carboxamide; or R3 and R4 together are alkylene or heteroalkylene attached to adjacent carbons of the phenyl to which R3 and R4 are attached, and R5 is as specified in (e) above;
(f) R6, R7 and R8 are each independently selected from the group consisting of hydrogen, halo, alkyl, aryl, heterocycle, nitro, cyano, and unsubstituted or alkyl- or aryl- or heterocycle-substituted hydroxy, thio, amino, amide, sulfonamide, formyl (acyl), carboxy, and carboxamide; or R6 and R7 together are alkylene or heteroalkylene attached to adjacent carbons of the phenyl to which R6 and R7 are attached, and R8 is as specified in (f) above;
(g) R9 is selected from hydrogen, halo, alkyl, aryl, heterocycle, and carboxy and its alkyl and aryl esters and amides;
(h) R10, R12 and R14, and R11, R13 and R15, if not nil, are each independently selected from hydrogen, alkyl, and aryl;
and an optical isomer, diestereomer or enantiomer thereof, a pharmaceutically acceptable salt, hydrate, or biohydrolyzable ester, amide or imide thereof.
The subject invention also includes compositions comprising a subject compound and a pharmaceutically-acceptable excipient; and methods for treating or preventing diseases or disorders by administering to a human or lower animal in need thereof, a safe and effective amount of a subject compound.
As used herein unless specified otherwise, xe2x80x9calkylxe2x80x9d means a hydrocarbon chain which is branched, linear or cyclic, saturated or unsaturated (but not aromatic), substituted or unsubstituted. The term xe2x80x9calkylxe2x80x9d may be used alone or as part of another word where it may be shortened to xe2x80x9calkxe2x80x9d (e.g., in alkoxy, alkylacyl). Preferred linear alkyl have from one to about twenty carbon atoms, more preferably from one to about ten carbon atoms, more preferably still from one to about six carbon atoms, still more preferably from one to about four carbon atoms; most preferred are methyl or ethyl. Preferred cyclic and branched alkyl have from three to about twenty carbon atoms, more preferably from three to about ten carbon atoms, more preferably still from three to about seven carbon atoms, still more preferably from three to about five carbon atoms. Preferred cyclic alkyl have one hydrocarbon ring, but may have two, three, or more, fused hydrocarbon rings. Preferred alkyl are unsaturated with from one to about three double or triple bonds, preferably double bonds; more preferably they are mono-unsaturated with one double bond. Still more preferred alkyl are saturated. Saturated alkyl are referred to herein as xe2x80x9calkanylxe2x80x9d. Alkyl unsaturated only with one or more double bonds (no triple bonds) are referred to herein as xe2x80x9calkenylxe2x80x9d. Preferred substituents of alkyl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted alkyl are preferred.
As used herein, xe2x80x9cheteroatomxe2x80x9d means a nitrogen, oxygen, or sulfur atom.
As used herein, xe2x80x9calkylenexe2x80x9d means an alkyl which connects two other moieties, xe2x80x9cheteroalkylenexe2x80x9d means an alkylene having one or more heteroatoms in the connecting chain.
As used herein unless specified otherwise, xe2x80x9carylxe2x80x9d means an aromatic hydrocarbon ring (or fused rings) which is substituted or unsubstituted. The term xe2x80x9carylxe2x80x9d may be used alone or as part of another word (e.g., in aryloxy, arylacyl). Preferred aryl have from six to about fourteen, preferably to about ten, carbon atoms in the aromatic ring(s), and a total of from about six to about twenty, preferably to about twelve, carbon atoms. Preferred aryl is phenyl or naphthyl; most preferred is phenyl. Preferred substituents of aryl include halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides, nitro, and cyano. Also, unsubstituted aryl are preferred.
As used herein unless specified otherwise, xe2x80x9cheterocyclexe2x80x9d means a saturated, unsaturated or aromatic cyclic hydrocarbon ring (or fused rings) with one or more heteroatoms in the hydrocarbon ring(s). Preferred heterocycles have from one to about six heteroatoms in the ring(s), more preferably one or two or three heteroatoms in the ring(s). Preferred heterocycles have from three to about fourteen, preferably to about ten, carbon plus heteroatoms in the ring(s), more preferably from three to about seven, more preferably still five or six, carbon plus heteroatoms in the rings(s); and a total of from three to about twenty carbon plus heteroatoms, more preferably from three to about ten, more preferably still five or six, carbon plus heteroatoms. Preferred heterocycles have one ring, but may have two, three, or more, fused rings. More preferred heterocycle rings include those which are one ring with 5 or 6 carbon plus heteroatoms in the ring with no more than three ring heteroatoms, no more than two of which are O and S. Still more preferred are such 5- or 6-ring atom heterocycles with one or two ring atoms being O or S and the others being C; or with one, two or three ring atoms being N and the others being C. Such preferred 5- or 6-ring atom heterocycles are preferably saturated, unsaturated with one or two double bonds, or aromatic. Such preferred 5- or 6-ring atom heterocycles are preferably a single ring; or fused with a 3- to 6-ring atom hydrocarbon ring which is saturated, unsaturated with one double bond, or aromatic (phenyl); or fused with another such 5- or 6-ring atom heterocyclic ring. Heterocycles are unsubstituted or substituted. Preferred heterocycle substituents are the same as for alkyl.
The subject invention involves compounds having the following structure: 
In structure 1, the bond between the xcex1 carbon and the xcex2 nitrogen can be either a single bond, in which case R2 and the H attached to the xcex1 carbon exist, or a double bond, in which case R2 and that H do not exist (are nil). This Cxcex1-Nxcex2 bond is preferably a single bond.
In structure 1, the bonds between carbons 5 and 6 and between carbons 6 and 7 can both be single bonds or one can be a double bond. If the C5-C6 bond is a double bond, R13 and R15 do not exist (are nil). If the C6-C7 bond is a double bond, R11 and R13 do not exist (are nil). Preferably, the C5-C6 and C6-C7 bonds are both single bonds.
In structure 1, R1 is selected from hydrogen, alkyl, aryl, and heterocycle. Preferred R1 include linear alkanyl having from 1 to about 6 carbon atoms, linear alkenyl having from 2 to about 6 carbon atoms, and branched and cyclic alkanyl and alkenyl having from 3 to about 6 carbon atoms, such alkenyl preferably having 1 double bond. Such preferred alkanyl and alkenyl are preferably unsubstituted, or substituted with phenyl, heterocycle having 5 or 6 ring atoms, carboxy and its C1-C6 alkyl and phenyl esters, or cyano. More preferably such alkanyl and alkenyl have up to about 7 carbon atoms, more preferably still up to 6 carbon atoms, still more preferably up to 4 carbon atoms. Most preferred R1 is unsubstituted methyl. Also preferred is R1 being hydrogen.
In structure 1, R2, if it exists, is selected from hydrogen, alkyl, alkylacyl, arylacyl, alkylsulfonyl, and arylsulfonyl. Preferred R2 is selected from hydrogen; C1-C6 alkyl, such alkyl being saturated or unsaturated with one double bond and unsubstituted or substituted with phenyl; C1-C6 alkylacyl, the alkyl being saturated or unsaturated with one double bond; and phenylacyl. More preferred is the alkyl portions of the aforementioned moieties being C1-C4 and saturated. More preferred still is R2 being methyl. Most preferred R2 is hydrogen.
In structure 1, R3, R4 and R5 are each independently selected from hydrogen, halo, alkyl, aryl, heterocycle, nitro and cyano; also from hydroxy, thio, amino, amide, formyl (acyl), carboxy, and carboxamide which are unsubstituted or substituted, preferably with alkyl or aryl or heterocycle; or R3 and R4 together are alkylene or heteroalkylene attached to adjacent carbon atoms of the phenyl ring, thereby forming a cycloalkyl or aryl or heterocycle ring which is fused to the phenyl ring (phenyl of carbons 1xe2x80x2-6xe2x80x2), and R5 is as defined above. Preferred R3, R4 and R5 are selected from hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl or aryl esters and amides; more preferably from hydrogen, halo, alkyl, alkoxy, phenoxy, thio, alkylthio, phenylthio, mono- or dialkylamino, mono- or diphenylamino, alkylacyl, and phenylacyl. Alkyl portions of such substituents are preferably about C1-C6, more preferably about C1-C4, more preferably still methyl or ethyl. Alkyl and phenyl R3, R4 or R5 substituents or portions of such substituents are preferably unsubstituted or substituted with from 1 to about 3 fluoro, more preferably unsubstituted. More preferred is for from one to three of R3, R4, and R5 being halo, the other(s) being hydrogen. Also more preferred is for from one to three of R3, R4 and R5 being methyl or ethyl, the other(s) being hydrogen. Also preferred is R3 being dialkylamino, the alkyls having from 1 to about 6 carbon atoms, preferably from about 1 to about 4 carbon atoms, and R4 and R5 being hydrogen, R3 preferably being attached to the 4xe2x80x2 carbon. More preferred still is for from one to three of R3, R4 and R5 being independently selected from F, Cl and Br, the other(s) being hydrogen; still more preferred, when two or three of R3, R4 and R5 are F, Cl or Br, they are the same. Also more preferred is from one to three of R3, R4 and R5 being unsubstituted methyl, the other(s) being hydrogen. Also more preferred is one or two of R3, R4 and R5 being trifluoromethyl, the other(s) being hydrogen or halo, and if halo, preferably fluoro. Also more preferred is one or two of R3, R4 and R5 being methoxy or trifluoromethoxy, the others being hydrogen or halo, and if halo, preferably fluoro.
Also preferred are R3 and R4, which are attached to adjacent carbon atoms of the phenyl ring, together being a saturated or unsaturated alkylene or heteroalkylene having from 1 to about 6 carbon atoms and from 0 to about 3 heteroatoms, thus forming a ring fused to the phenyl, such ring having from about 5 to about 8 ring atoms. Such ring fused to the phenyl preferably has from about 5 to about 6 ring atoms of which from 0 to 2, more preferably 0 or 1, are heteroatoms. Preferred fused rings (including the phenyl to which R3 and R4 are attached) include naphthyl, indolyl, benzimidazoyl, benzofuryl, benzopyranyl. When R3 and R4 form a ring fused with the phenyl, R5 is preferably H.
In structure 1, R6, R7 and R8 are each independently selected from hydrogen, halo, alkyl, aryl, heterocycle, cyano and nitro; also from hydroxy, thio, amino, amide, formyl (acyl), carboxy, carboxamide, and sulfonamide which are unsubstituted or substituted, preferably with alkyl or aryl or heterocycle; or R3 and R4 together are alkylene or heteroalkylene attached to adjacent carbon atoms of the phenyl ring, thereby forming a cycloalkyl or aryl or heterocycle ring which is fused to the phenyl ring (phenyl of carbons 7-10), and R5 is as defined above. Preferred R6, R7 and R8 are selected from hydrogen, halo, alkyl, aryl, heterocycle, hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, amide, alkylamide, arylamide, sulfonamide, alkylsulfonamide, arylsulfonamide, formyl, alkylacyl, arylacyl, carboxy and its alkyl and aryl esters and amides; more preferably from hydrogen, halo, hydroxy, C1-C4 alkoxy, thio, C1-C4 alkylthio, C1-C4 alkyl esters and amides of carboxy, and heterocycle having 5 or 6 ring atoms. More preferably one or two of R6, R7 and R8 are selected such that at least one heteroatom is bonded directly to the phenyl ring. When two heteroatoms are bonded directly to different carbons, preferably adjacent carbons, of the phenyl ring, those heteroatoms may be connected by an alkylene moiety, the alkylene moiety preferably having from 1 to about 4, more preferably 1 or 2, carbon atoms. Preferred is for one or two of R6, R7 and R8 being non-hydrogen moieties bonded to the fused rings at carbons 8 and/or 9 (as in structure 2 below); more preferred is that two of them be non-hydrogen moieties bonded to carbons 8 and 9. More preferred still is that R8 is hydrogen and that R6 and R7 are both alkoxy or both alkylthio bonded to carbons 8 and 9, respectively; preferably both R6 and R7 are the same. Preferred alkyl portions of R6 and R7 have from 1 to about 4 carbon atoms, more preferably 1 or 2 carbon atoms; most preferred is methyl. Such alkyl portions are preferably unsubstituted. Such alkyl portions are preferably saturated. Most preferred is that both R6 and R7 are methoxy bonded to carbons 8 and 9, R8 being hydrogen.
Also preferred are R6 and R7, which are attached to adjacent carbon atoms of the phenyl ring, together being a saturated or unsaturated alkylene or heteroalkylene having from 1 to about 6 carbon atoms and from 0 to about 3 heteroatoms, thus forming a ring fused to the phenyl, such ring having from about 5 to about 8 ring atoms. Such ring fused to the phenyl preferably has from about 5 to about 6 ring atoms of which from 0 to 2, more preferably 0 or 1, are heteroatoms. Preferred rings formed by R6 and R7 include phenyl, furyl, pyrrolyl, dioxanyl, imidazoyl, pyridinyl, pyrrolidinyl, piperidinyl. When R6 and R7 form a fused ring, R8 is preferably H.
In structure 1, R9 is selected from hydrogen, halo, alkyl, aryl, heterocycle, carboxy and its alkyl esters and amides. Preferred R9 is selected from hydrogen, halo, C1-C4 alkyl, phenyl. More preferred R9 is selected from hydrogen and unsubstituted and substitituted phenyl; substituents on such phenyl are preferably selected from hydroxy, alkoxy, thio and alkylthio. Most preferred R9 is hydrogen.
In structure 1, R10, R12 and R14, and R11, R13 and R15 if they exist, are each independently selected from hydrogen, alkyl and aryl. Preferred R10, R12 and R14, and R11, R13 and R15 if they exist, are selected from hydrogen and alkyl having from 1 to about 4 carbon atoms, especially unsubstituted methyl or ethyl. Most preferred is for R10, R12 and R14, and R11, R13 and R15 if they exist, to all be hydrogen.
The subject invention includes optical isomers, diastereomers, and enantiomers of the compounds of structure 1. The subject invention includes pharmaceutically-acceptable salts, hydrates, and biohydrolizable esters, amides and imides of such compounds.
A xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d is a cationic salt formed at any acidic group (e.g., carboxy group), or an anionic salt formed at any basic group (e.g., amino group) on a compound of structure 1. Many pharmaceutically-acceptable salts are known. Preferred cationic salts include the alkali metal salts, such as sodium and potassium, alkaline earth metal salts, such as magnesium and calcium, and organic salts, such as ammonium. Preferred anionic salts include halides, sulfonates, carboxolates, phosphates, and the like. Salts of addition may provide an optical center where once there was none.
The compounds of the subject invention, and salts thereof, may have one or more chiral centers. The invention includes all optical isomers of the compounds of structure 1 and salts thereof, including diastereomers and enanteomers The subject invention includes and contemplates each optical isomer, diastereomer or enanteomer thereof, in purified form, substantially purified form, and mixtures, including racemic mixtures.
For compounds of structure 1 having a single Cxcex1-Nxcex2 bond and different R1 and R2 moieties, the xcex1 carbon is stereogenic. For such compounds, those having the R stereoscopic configuration are generally preferred over those having the S configuration.
Preferred compounds of the subject invention include those having structure 2: 
in structure 2, R1, R6, and R7 are as described hereinabove, and Y is the combinations of R3, R4 and R5 described hereinabove.
In structure 2, R1 is preferably selected from linear alkanyl having from one to four carbon atoms, linear alkenyl having one double bond and from two to four carbon atoms, branched and cyclic alkanyl having from three to five carbon atoms, and branched and cyclic alkenyl having one double bond and from three to five carbon atoms. Such preferred R1 are unsubstituted or substituted with one phenyl, more preferably are unsubstituted. More preferred R1 is selected from methyl, ethyl, ethenyl, n-propyl, i-propyl, n-propenyl, i-propenyl, s-butyl, cyclopropyl, cyclobutyl, and cyclopentyl. More preferred still R1 is selected from methyl, ethyl, ethenyl, i-propyl, and n-propenyl. Most preferred R1 is methyl.
In structure 2, one or both of R6 and R7, preferably both, are preferably alkylthio or more preferably alkoxy with alkanyl having from one to four carbon atoms. If one of R6 and R7 is not alkylthio or alkoxy, it is preferably hydrogen. More preferred is both R6 and R7 being methoxy or ethoxy; most preferred is both R6 and R7 being methoxy.
In structure 2, Y is preferably selected from all hydrogen; mono-, di-, or trihalo, preferably selected from fluoro, chloro and bromo, preferably in one or more of the 2xe2x80x2, 3xe2x80x2, 4xe2x80x2 and 5xe2x80x2 positions; mono- di-, and trimethyl, preferably in one or more of the 2xe2x80x2, 3xe2x80x2, 4xe2x80x2 and 6xe2x80x2 positions; and mono- or di-trifluoromethyl, preferably in one or both of the 3xe2x80x2 and 5xe2x80x2 positions. Also preferred is Y being diakylamino, preferably in the 4xe2x80x2 position, the two alkyls preferably being the same and preferably having from 1 to 4 carbon atoms. More preferred Y is selected from 4xe2x80x2-fluoro, 4xe2x80x2-chloro, 4xe2x80x2-bromo, 2xe2x80x2,4xe2x80x2-difluoro, 2xe2x80x2,4xe2x80x2-dichloro, 2xe2x80x2,4xe2x80x2-dibromo, 2xe2x80x2,4xe2x80x2,5xe2x80x2-trifluoro, 2xe2x80x2,4xe2x80x2,5xe2x80x2-trichloro, 3xe2x80x2,4xe2x80x2-difluoro, 3xe2x80x2,4xe2x80x2-dichloro, 3xe2x80x2,4xe2x80x2-dibromo, 4xe2x80x2-methyl, 2xe2x80x2,4xe2x80x2-dimethyl, 2xe2x80x2,4xe2x80x2,6xe2x80x2-trimethyl, 3xe2x80x2-trifluoromethyl, 3xe2x80x2,5xe2x80x2-di-trifluoromethyl, and 4xe2x80x2-dibutylamino. Also preferred Y is selected from 2xe2x80x2,4xe2x80x2-dihalo and 3xe2x80x2,4xe2x80x2-dihalo, where one halo is selected from fluoro, chloro, and bromo, and the other halo is a different one of those three; more preferably one of such halo is fluoro. Most preferred Y is selected from 4xe2x80x2-cholor, 4xe2x80x2-bromo, and 2xe2x80x2,4xe2x80x2-dichloro.
Non-limiting examples of compounds of the subject invention include those of structure 2 wherein R6 and R7 are both methoxy, and R1 and Y are as indicated in the following table:
In addition, it is recognized that for purification, administration, and the like, the salts and other derivatives of the above compounds can be used. Thus a pharmaceutically-acceptable salt, hydrate, or biohydrolizable ester, amide or imide thereof is contemplated as part of the subject invention.
In making the compounds of the subject invention, the order of synthetic steps may be varied to increase yield of desired product. The skilled artisan will recognize that the judicious choice of reactants, solvents, and temperatures is important in successful synthesis. The starting materials used in preparing the subject compounds are known, made by known methods, or are commercially available.
It is recognized that the skilled artisan can readily carry out standard manipulations of organic compounds without further direction. These include, but are not limited to, reduction, oxidation, acylation, substitution, etherification, esterification, sulfonation, and the like. Examples of these manipulations are discussed in standard texts.
Procedures for preparing some imidazo-isoquinoline comopounds are disclosed in U.S. Pat. No. 3,917,610 issued Nov. 4, 1975, and U.S. Pat. No. 4,143,143 issued on Mar. 6, 1979, both of which are incorporated herein by reference.
The following general schemes can be used for synthesizing compounds of the subject invention. 